The molecular mechanisms by which the immune system discriminates self from non-self are not understood. The breakdown of these mechanisms can result in autoimmune disease. CD4+ helper T (Th) cells are key regulatory players in various forms of autoimmune disease. Th cell activation, differentiation and function are regulated by costimulatory molecules. CD28, a receptor for B7 gene products, plays a major role in initiating T cell immune responses. CTLA4, which binds B7 with a higher affinity, is induced after T cell activation and plays a role in down-regulating T cell responses. PD-1 is an inhibitory receptor for a B7 homologue, B7-Hl. Mice deficient in PD-1 develop dilated cardiomyopathy and lupus-like proliferative arthritis and glomerulonephritis. Inducible co-stimulator (ICOS), a third member of the CD28/CTLA4 family, is expressed on activated T cells. Its ligand, B7H, is another B7-homologue expressed on B cells and induced in nonlymphoid tissues by tumor necrosis factor (TNF). Recently, we generated and analyzed ICOS-deficient mice. ICOS is required for humoral immune responses after immunization with several antigens. ICOS-/- mice exhibited greatly enhanced susceptibility to experimental autoimmune encephalomyelitis (EAE), suggesting that ICOS plays a preventative role in inflammatory autoimmune diseases. Thus, members of the B7 costimulator family play essential roles in immune activation and function. We are particularly interested in the new members of this family that engage receptors on activated T cells and are also expressed in nonlymphoid tissues. We hypothesize that these molecules provide mechanisms by which T cell function and tolerance are regulated in the effector phase. We propose to study immune regulation by these B7 homologues. We will determine the role B7H plays in regulation of humoral immunity and autoimmunity and test if B7H expressed on B cells stimulates T-cell help for humoral immunity and autoimmunity. We will define the site and phase during EAE autoimmunity in which ICOS functions to contain inflammation, and assess if B7H expressed by inflamed tissues during the effector phase of EAE provides a protective mechanism of peripheral tolerance. B7JH is a novel member of the B7 family we discovered that is most homologous to B7-H1. B7JH is restrictedly expressed in the liver. We will determine if B7JH is a second ligand for PD-1, and construct B7JHI-deficient animals to assess its function in immune tolerance in the liver. These studies will advance our knowledge of the regulation of T-cell function and tolerance, and may lead to a greater understanding of autoimmune diseases.